CA2167039C - Alkylated (hetero)cyclic compounds; process for preparing the same and pharmaceutical compositions containing them - Google Patents

Abstract

Hetero-cycloalkyl derivs. of formula (I) and their enantiomers and diastereoisomers are new. R1 = alkyl opt. substd. by Q; or cycloalkyl or cycloalkylalkyl, both opt. substd. by Q'; A together with the benzene gp. = tetrahydronaphthalene, dihydronaphthalene, naphthalene, benzothiophene, 2,3-dihydrobenzothiophene; or indoline or indole both opt. N-substd. by Ra, CORa or CO2Ra; Ra = alkyl, Ph or phenylalkyl; R2 = H or alkyl; R3 = C(=X)R4 or C(=X')NHR5; X, X' = S or O; R4 = H, alkenyl, alkynyl, alkyl opt. substd. by Q, or cycloalkyl or cycloalkylalkyl both opt. substd. by Q'; R5 = H, alkyl opt. substd. by Q, or cycloalkyl or cycloalkylalkyl both opt. substd. by Q'; alkyl, alkoxy = 1-6C; alkenyl, alkynyl = 2-6C; cycloalkyl = 3-8C; Q = halo, OH, alkyl or alkoxy; Q' = halo, alkyl or oxo.

Description

ALKYLATED (HETERO) CYCLIC COMPOUNDS, THEIR PREPARATION PROCESS AND THE COMPOSITIONS
PHARMACEUTICALS THAT CONTAIN THEM
The invention relates to new (hetero) alkylated compounds, their procédé.de preparation and pharmaceutical compositions containing them.
The invention describes novel alkylated (hetero) cyclic compounds which turn out to be powerful melatoninergic receptor ligands.
Many studies have shown over the past ten years, the role capital melatonin (5-methoxy N-acetyl tryptamine) in rhythm control circadian and endocrine functions, and melatonin receptors have been characterized and located.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg 1o 63, pp 321-341) and sleep (Psychopharmacology, 1990, 100, pp 222-226), ligands of the melatoninergic system have interesting properties pharmacological on central nervous system, including anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesics (Pharmacopsychiat., 1987, 20, pp 222-223) as well as for the treatment of Parkinson's disease (J.
Neurosurg 1985, 63, pp 321-341) and Alzheimer's (grain Research, 1990, 528, pp 170-174). Of even, these compounds have shown activity on certain cancers (Melatonin - clinicat outlook Oxford University Press, 1988, pp 164-165), on ovulation (Science 1987, 227, pp 7i 4-720), and on diabetes (Clinicat endocrinolgy, 1986, 24, pp 359-364).

216'T ~~ 9 Compounds making it possible to act on the melatoninergic system are therefore for the clinician excellent drugs for the treatment of pathologies mentioned previously.
The invention relates to the compounds of formula (I) a CH2 CH2 N-R3 b R ~ IA OI
c ~
d in which - R1 represents a radical chosen from alkyl, substituted alkyl, cycloalkyl, cycloalkyl-substituted, cycloalkylalkyle, and substituted cycloalkylalkyle, - Has a cyclic group with the benzene ring to which it is linked selected 1o among tetrahydronaphthalene, dihydronaphthalene, naphthalene, benzothiophene,

2.3 dihydrobenzothiophene, indoline, substituted indoline, indole and indole substituted - R2 represents a hydrogen or an alkyl, - R3 represents ~ an R31 group:
-ë-Ra ~ R31 ~
with X representing a sulfur or an oxygen and R4 representing a hydrogen or a radical R41 chosen from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl and substituted cycloalkylalkyl, ~ or a group of formula (R32):
- ~ -NH-RS ~ R32 ~
with X 'representing a sulfur or an oxygen and R5 representing a hydrogen or a radical chosen from alkyl, substituted alkyl, cycloalkyl, cycloalkyl substituted cycloalkylalkyle and substituted cycloalkylalkyle, it being understood that during the description of the formula (I), and unless otherwise mentioned opposite 2s - the terms "alkyl" and "alkoxy" denote linear groups or branched containing from 1 to 6 carbon atoms, the terms "alkenyl" and "alkynyl" denote linear groups, or branched containing from 2 to 6 atoms, the term "cycloalkyl" denotes a group of 3 to 8 carbon atoms,

3 ~ ~ 6? OJ '~
the term "substituted" associated with the alkyl radical means that this radical is substituted by one or more substituents chosen from halogen, "alkyl", hydroxy and alkoxy, the term "substituted" associated with the radical "cycloalkyl" and "cycloalkylalkyle" means that this radical is substituted by one or several radicals or groups chosen from halogen, alkyl and oxo, - the term "substituted" associated with the terms "indole" and "indoline"
means that these groups are substituted on nitrogen by position 1 by a radical chosen from -Ra, -CO-Ra and -CO-O-Ra in which Ra represents a phenyl alkyl radical or phenylalkyl, and their enantiomers and diastereoisomers.
The invention particularly relates to the compounds of formula (I) in which, taken separately or together, - R, represents an alkyl, - R, represents a (CZ-C6) alkyl, - R, represents an ethyl, R, represents a propyl, - R, represents a butyl, - Forms with the benzene nucleus to which it is linked a naphthalene, - Forms with the benzene nucleus to which it is linked a benzothiophene, - Has an indole with the benzene nucleus to which it is linked, - Has an indole with the benzene nucleus to which it is linked substituted - R2 represents hydrogen, RZ represents an alkyl, - R3 represents an R3 group, as defined in formula (I) - R3 represents an R32 group as defined in formula (I) - R4 represents a hydrogen atom, - R4 represents an alkyl, - R4 represents a cycloalkyl, - R4 represents an alkenyl, - R5 represents a hydrogen, ~~~ 1039

4 R5 represents an alkyl, - R5 represents cycloalkyl, - X represents oxygen, - X represents a sulfur, - X 'represents an oxygen, - or X 'represents a sulfur.
For example, the invention relates to particular compounds of formula (I) corresponding to the respective formulas (1) to (3) RZ
CHZ CHz N-R3 Ry R ~
g ' C1) (2) RZ

R ~ _ J
NOT
H
~ 3) The invention particularly relates to the compounds of formula (I), for example the particular compounds of formula (1) to (3), as defined this-above in which R ~ is - in position a of the benzene ring, - in position b of the benzene ring, - in position c of the benzene ring, - or in position d of the benzene ring.
For example, the invention relates to the compounds of formula (I) in which R, is in position b of the benzo nucleus.
In particular, the invention relates to the following compounds - N- [2- (5-ethyl benzothiophen-3-yl) ethyl] acetamide, - N- [2- (5-ethyl benzothiophen-3-yl) ethyl] cyclobutanecarboxamide, - and N- [2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) ethyl] trifluoro-

5 acetamide.
In particular, the alkyl radicals present in the formula (I) can be chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl.
The alkoxy radicals present in formula (I) can be chosen from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The halogens present in formula (I) can be chosen among bromine, chlorine, fluorine, and iodine.
The cycloalkyls present in formula (I) can be chosen among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The invention also relates to the process for preparing compounds of formula (I) characterized in that reacting a compound of formula (II) I
CHZ-CHZ-N H
R ~ A (II) in which R, and A are as defined in formula (I), - either with formic acid or with a compound of formula (Illa) or (IIIb) ~ i 2167 ~ 3 ~

6 Hal- ~ - R4 ~ (Illa) O
R4 ~ ~ -O- ~ -R4 ~ (Illb) OO
in which R41 is as defined in formula (I) and Hal represents a halogen so to obtain the compounds of formula (1 / a) CH2 CHZ N- ~ -R4 R1 IA _- O (fia) in which R1, R2, R4 and A are as defined above., compounds of formula (1 / a) subjected to the Lawesson reagent to obtain the compounds of formula (1 / a ') CH2 CH2 N- ~ -R4 R ~ IAS (fia ') in which R1, R2, R4 and A are as defined above, 1o - either with a compound of formula (IV) X '= C = N-RS (IV) in which X 'and R5 are as defined in formula (I) in order to obtain the compounds of formula (1 / b) CH2 CH2 N- ~ -NH-R5 X
R, IA
t5 in which R ~, R2, R5, A and X 'are as defined above, ~~ f ~ 703 the compounds of formula (1 / a), (1 / a ') and (1 / b) forming all of the compounds of formula (I), compounds of formula (I) which are, where appropriate, separated into their different enanthiomers or diastereoisomers.
For example, the invention also extends to the method of preparation of the compounds of formula (1 / f) RZ
R / CHz-CHz-N-R3 ~ S
(lift in which R ,, Rz and R3 are as defined in formula (I), characterized in that:

8 ~ '. ~ 6 ~ OJ9 reacting a compound of formula (11 / b) RZ
R / CHz-CH2 -NH
y ~ b>
s in which R, and RZ are as defined above, - either with a compound of formula (Illa) or (Illb) as defined previously, in order to obtain the compounds of formula (1 / g) ~~ ~~ 61Q

'~ ~ N9) J
S
in which R1, R2 and R4 are as defined above, which are then submitted to Lawesson's reagent to obtain the compounds of formula (1 / g ') RZ

S (U9.) J
S
in which R1, R2 and R4 are as defined above, - either with a compound of formula (IV) as defined above, in order to obtain the compounds of formula (1 / h) R CH2 CHz NC-NH-R5 X '(~) J
S
in which R1, R2, R5 and X 'are as defined above, the compounds of formula (1 / g), (1 / g ') and (1 / h) forming all of the compounds of formula (1 / f), the compounds of formula (1 / f) which can be separated into their different enantiomers or diastereoisomers.
The raw materials used in the previously described processes are is be readily accessible to those skilled in the art from the literature and examples of preparations given below.
For example, it is possible to prepare the compounds of formula (11 / a) R ~ (IUa) ~~ i ~: ~? lJ ~~
in which R ~ and R2 are as defined in formula (I), by reaction of a compound of formula (V) /
R ~ ~ (V) in which R1 is as defined above with succinic anhydride to get a compound of formula (V1) /
R, ~ O
II CH2 CH2 C \ (V1) O OH
in which R ~ is as defined above, which is reduced to obtain a compound of formula (VII) /
R '\ I CH-CH-CH-C ~~ O (VII) zzz OH
to in which R ~ is as defined above, which is then cyclized to obtain a compound of formula (VIII) O
/
R ~ I (VIII) in which R1 is as defined above, which is reacted with diethyl cyanomethyl phosphonate to get the compound of formula (IX) CN
I
CH
R ~ I (IX) in which R1 is as defined above, ~ 6 ~ 0 ~~
which is then hydrogenated to obtain the compound of formula (11 / c) (IUC) in which R1 is as defined above, compound of formula (11 / c) optionally alkylated on the amine function for obtain a compound of formula (11 / d) (II / d) in which R1 is as defined above and R'2 represents a radical (C1 Cg) alkyl, the compounds of formula (11 / c) and (11 / d) forming all of the compounds of formula (11 / a), 1o the compounds of formula (11 / a) which can be separated into their enantiomers or diastereoisomers and salified with a pharmaceutically acceptable acid.
The aromatization of compounds with a tetrahydronaphthalene structure such as described above makes it possible to obtain the compounds useful for the preparation of composed of formula (I) in which A forms with the benzene ring to which it is linked a group naphthalene.
Another example of preparation of the compounds of formula (II) consists in the process for preparing the compounds of formula (11 / e) (UIE) J
G
in which R1 and R2 are as defined in formula (I) and G
represents sulfur or 2o an -NH group, 2 ~. ~ '~ 0 ~ 9 characterized in that a compound of formula (X) is reacted i Ri I (X) GH
in which R1 and G are as defined above, with ethyl 4-chloroacetoacetate to obtain the compound of formula (X1) O
//
O / CH2 C \
CO
R, \ I / CH ~ _CHZ CH3 (X1) in which R1 and G are as defined above, which we cycle, to get a compound of formula (X11), CH21 i ~ OwCH2 CH3 R '~ IJO _ (X11) G
in which R1 and G are as defined above, which are hydrolyzed to get the 1o compound of formula (X111) CH2, C ~ OH
R / II ~ (X111) '~ J
G
in which R1 and G are as defined above, which is amidified to get a compound of formula (XIV) O
ii CHZ C \
NH2 (XIV) R '~ IJ
G
in which R1 and G are as defined above, which are dehydrated in nitrite then which is then reduced to obtain a compound of formula (11 / f) (IUF) R, ~ II
G ~
in which R1 and G are as defined above, 2 ~ 67 ~ 39 compound of formula (11 / e) optionally alkylated on the amine function for obtain a compound of formula (11 / g) R'2 I

R, (~ (191 G
in which R1 and G are as defined above and R'2 represents a radical (C1-Cg) alkyl, the compounds of formula (11 / f) and (11 / g) forming all of the compounds of formula (11 / d), the compounds of formula (11 / e) which can be salified with an acid pharmaceutically acceptable.
More particularly, the preparation of the compounds of formula (11 / d) is accessible when G
represents sulfur.
Among the pharmaceutically acceptable acids which can be used for form an addition salt with the compounds of formula (II), there may be mentioned as examples and without limitation, hydrochloric, sulfuric, phosphoric acids, tartaric, malic, malefic, fumaric, oxalic, methanesulfonic, ethanesulfanic, camphoric, and citric.
The compounds of formula (I) have very pharmacological properties interesting to the clinician.
The compounds of the invention and the pharmaceutical compositions containing them prove to be useful for the treatment of system disorders melatoninergic.
2o The pharmacological study of the compounds of the invention has indeed shown they were not toxic, endowed with a very high selective affinity for receptors melatonin and had important activities on the nervous system central and in in particular, therapeutic properties have been noted in sleep, anxiolytic, antipsychotic, analgesic properties as well as microcirculation which make it possible to establish that the products of the invention are useful in the stress treatment, sleep disturbances, anxiety, seasonal depressions, pathologies cardiovascular, insomnia and fatigue due to jet lag, the schizophrenia, panic attacks, melancholy, disorders of appetite, obesity, insomnia, psychotic disorders, epilepsy, disease 3o Parkinson's, senile dementia, various disorders related to normal aging ~ or pathological, migraine, memory loss, disease Alzheimer's, as well as 14 ~~~ 7 ~~~
cerebral circulation disorders. In another field of activity, it appears that products of the invention have properties of ovulation inhibitors, immunomodulators and are likely to be used in the treatment cancer.
The compounds will preferably be used in the treatment of depressions sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jet lag, appetite disturbances and obesity.
For example, the compounds will be used in the treatment of depression seasonal and sleep disturbances.
to The present invention also relates to the compositions pharmaceutical containing the products of formula (I) in combination with one or more excipients pharmaceutically acceptable.
Among the pharmaceutical compositions according to the invention, mention may be made of, more especially those suitable for oral administration, parenteral, nasal, per.
or transcutaneous, rectal, perlingual, ocular or respiratory and in particular tablets simple or coated, sublingual tablets, sachets, packages, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of Directors the nature of the therapeutic indication, or any treatments associates and ranges from 0.1 mg to 1 g per 24 hours in 1 or 2 presses, plus particularly between 1 at 100 mg, for example between 1 to 10 mg.
The following examples illustrate the invention, but do not limit it in any way.
way.
PREPARATION 1: 2- (7-ETHYL-1,2,3-4-TETRAHYDRONAPHT-1-YL) ETHYLAMINE
STAGE A: 4-OXO-4- (4-ETHYL-PHENYL) ACID BUTYRIG1UE
Reagents Ethyl benzene: 0.05 mole (5 cm3) Aluminum chloride: 0.02 mole (2.6 g) Succinic anhydride: 0.01 mole (1 g) -Procedure In a 50 cm3 flask, mix with magnetic stirring 5 cm3 of ethyl benzene and 2.6 g of aluminum chloride. Cool the solution in a bath ice then add 1 g succinic anhydride. Shake for 1 hour 30 minutes at 0 ° C then 3 h at ambient temperature.
Pour the reaction mixture into ice.
Acidify by adding 1N hydrochloric acid (pH 3-4). Extract by 3 volumes of ether. The organic phases are washed 3 times with a carbonate solution of 10% potassium.
The aqueous phases are combined and acidified by adding acid hydrochloric io concentrated.
The precipitate obtained is drained and then recrystallized.
Characteristics 206.23 g / mole for C12H1403 White powder Melting temperature: 106-108 ° C
Rf = 0.36 eluent: acetone-toluene-cyclohexane (2-2-1) Recrystallization solvent: cyclohexane Yield: 57 ab z CD

O
2o Infrared spectroscopic analysis 2960-2920 cm-1: v CH alkyls 1710 cm-1: v acidic CO

1670 cm-1: v CO ctone 1600 cm-1: v C = C aromatic 2s Spectroscopic analysis of proton NMR (80 MHz, DMSO dg, S) 1.2 ppm (triplet, CH3 (a) Ja_b - 6.60 3H): Hz 2.6 ppm (multiplet, CH2 (b) and CH2 Jb-a = Jd-c6.60 4H): (d) = Hz 3.2 ppm (triplet, CH2 (c) Jc-d - 6.60 2H): Hz

7.4 ppm (doublet, H3 and H5 Jortho - g, 80 2H): Hz 30 7.9 ppm (doublet, H2 and H6 Jortho - 8.80 2H): Hz 12.1 ppm (multiplet, COOH
1 H):

Mass spectrometric analysis m / e 206: M +
m / e 207: (M + 1) +
STAGE B: ACID 4- (4-ETHYL-PHENYL) BUTYRICIUE
ab cde Reagents 4-oxo-4- (4-ethyl-phenyl) butyric acid (stage A): 0.012 mole (2.5 g) Triethylsilane: 0.028 mole (3.2 g) Trifluoroacetic acid: 0.12 mole (19 cm3) 1o Procedure In a 100 cm3 flask, 2.5 g of 4-oxo-4- (4-ethyl-phenyl) butyric acid are dissolved with magnetic stirring in 19 cm3 of trifluoroacetic acid.
Add drop to 3.2 g of triethylsilane.
Shake for 86 hours at room temperature. , ts The reaction mixture is poured into ice.
Extract with 3 volumes of ether. The organic phases are washed 3 times with a solution of 10% potassium carbonate. The aqueous phases are collected then acidified by addition of concentrated hydrochloric acid, up to pH 3-4.
The precipitate obtained is drained and then recrystallized.
2o Characteristics 192.25 g / mole for C12H1602 White powder Melting temperature: 71-73 ° C
Rf = 0.67, eluent: acetone-toluene-cyclohexane (2-2-1) 2s Recrystallization solvent: water Yield: 65 Infrared spectroscopic analysis 3280-2780 cm-1: v OH acid 2940-2850 cm-1: v CH alkyls 30 1680 cm-1: v acidic CO

21 ~ '~~ ~ i 9 1510 cm-1: v C = C aromatic Proton NMR spectroscopic analysis (300 MHz, DMSO dg, 8) 1.14 ppm (triplet, 3H) CH3 (a) Ja-b = T, 63 Hz :

1.76 ppm (multiplet, CH2 (d) 2H):

2.20 ppm (triplet, 2H) CH2 (e) Jd_e = 7.65 Hz :

2.55 ppm (multiplet, CH2 (c) and CH2 (b) 4H):

7.11 ppm (multiplet, aromatic H
6H):

OH acid no observed Analysis spectromtrique massive 1 om / e 192: M +

m / e 193: (M + 1) +

STAGE C: 7-ETHYL TETRAL-1-ONE
ab O

6 ~ '' 3 Reagents 4- (4-ethylphenyl) butyric acid (stage B): 0.013 mole (2.5 g) Polyphosphoric acid: 25 g Procedure Pour 25 g of polyphosphoric acid into a 100 cm3 flask with a ground neck.
Add 2.5 g of 4- (4-ethylphenyl) butyric acid. Shake for 6 hours temperature of 45 ° C. The 2o reaction mixture is poured into ice. Extract by 3 volumes of ether. The phases organics are washed 3 times with a 10% potassium carbonate solution %, dried over magnesium sulfate and then evaporated to dryness.
The oil obtained is purified by column chromatography.
Characteristics 174.23 g / mole for C12H140 Colorless oil Rf = 0.35 eluent: toluene-cyclohexane (1-2) Yield: 55 18 ~ 1 ~ 7039 Infrared spectroscopic analysis 3010 cm-1: v aromatic CH
2980-2860 cm- ~: v CH alkyls 1680 cm-1: v CO ketone 1605 cm'1: v C = C aromatic Proton NMR spectroscopic analysis (300 MHz, DMSO dg, 8) 1.13 ppm (triplet, 3H): CH3 (a), Ja_b = 7.68 Hz 2.01 ppm (multiplet, 2H) CH2 (3) :

2.59 ppm (multiplet, 4H) CH2 (b) and CH2 (4) :

2.88 ppm (triplet, 2H): CH2 (2), J2_3 = 5.77 Hz 7.25 ppm (doublet, 1 H): H5, Jortho = 8.59 Hz 7.39 ppm (doublet doubled, H6, Jortho = 8.59 Hz, Jmta =
1 H): 2.14 Hz 7.70 ppm (doublet, 1 H): Hg, Jmta = 2.14 Hz Mass spectrometric analysis m / e 174: M +
m / e 175: (M + 1) +
STAGE D: 2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-YLIDEN-1-YL) ACETONITRILE
H ~ c, CN NÇ c / H
ab C ab C

6 ~ 3 6 ~ 3 Isomer E (85%) Isomer Z (15%) Reagents 7-Ethyl tetralone (stage C): 0.029 mole (5 g) Diethyl cyanomethyl phosphonate: 0.048 mole (8.9 g) Sodium hydride: 0.048 mole (1.12 g) Anhydrous tetrahydrofuran: 20 cm3 Procedure In a knitted 100 cm3 flask, bubbled nitrogen gas into 20 cm3 of anhydrous tetrahydrofuran. 1.15 g of sodium hydride are added under agitation magnetic then diethyl cyanomethyl phosphonate, drop by drop.

19 X16? ~ 39 The reaction medium is stirred for 1 h at room temperature, until the end of the clearance gaseous.
Add 7-ethyl tetralone then continue stirring for 24 h at temperature room, under stream of nitrogen gas.
Pour the reaction mixture into ice.
Extract with 3 volumes of ether. The organic phases are washed 3 times at water, dried over magnesium sulfate and then evaporated to dryness.
The oil obtained is purified by column chromatography.
Characteristics 197.27 g / mole for C14H15N
Colorless oil Rf = 0.60, eluent: acetone-toluene-cyclohexane (5-3-2) Yield: 60 Analysis spectroscopic in infrared 3050 cm-1: v aromatic CH

cm-1 : v CH alkyls 2200 cm-1: v CN

1585 cm-1: v C = C aromatic Analysis spectroscopic of NMR
proton (300 MHz, DMSO
dg,

8) 2o Isomre E

1.22 ppm (triplet, 3H): CH3 (a), Ja_b = 8.04 Hz 1.94 ppm (multiplet, 2H): CH2 (3) 2.66 ppm (multiplet, 2H): CH2 (2) 2.87 ppm (multiplet, 4H): CH2 (b) and CH2 (4) 5.73 ppm (singlet, 1 H): CH (c) 7.08 ppm (doublet, 1 H): H5, Jortho = 776 Hz 7.16 ppm (multiplet, 1 H): H6, = 7.76 Hz Jortho 7.36 ppm (multiplet, 1 H): Hg Isomre Z

1.22 ppm (triplet, 3H): CH3 (a), Ja-b = 8.04 Hz 1.94 ppm (multiplet, 2H): CH2 (3) 2.66 ppm (multiplet, 2H): CH2 (2) 2.87 ppm (multiplet, 4H): CH2 (b) and CH2 (4) 5.23 ppm (singlet, 1 H): CH (c) 20 21s' ~~ 39 7.08 ppm (doublet, 1 H): H5, ~ ortho = 7.76 Hz 7.16 ppm (multiplet, 1 H): H6, ~ ortho = 7.76 Hz 8.14 ppm (multiplet, 1 H): H8 STAGE E: (R, S) 2- (7-ETHYL-1,2,3,4-TETRAHYDRO-NAPHT-1-YL) ETHYLAMINE
d ab ~ ~ NH2 6 ~ 3 Ractifs 2- (7-Ethyl-1,2,3,4-ttrahydronapht-ylidn-1-yl) actonitrile (stage D): 0.015 mole (3 g) Absolute alcohol: 150 cm3 1o Raney nickel: 0.5 g Hydrogen: 60 Bars Procedure In a 250 cm3 autoclave, dissolve 3 g of 2- (7-ethyl-1,2,3,4-tetrahydronaphth ylidèn-1-yl) acetonitrile in 150 cm3 of absolute alcohol. Add 0.5 g of Raney nickel.
~ 5 Shake for 6 hours at 60 ° C under a hydrogen pressure of 60 Bars.
Filter under vacuum. The filtrate is evaporated to dryness.
The residue is taken up in a small volume of ether saturated with hydrochloric acid gaseous. The the precipitate which forms is drained and then recrystallized.
Characteristics (hydrochloride) 20,239.78 g / mole for C14H22CIN
White powder Melting temperature: 116-118 ° C
Rf = 0.73, in acetone-toluene-cyclohexane-triethylamine (5-3-2- ~ 1) Yield: 49 25 Recrystallization solvent: ethyl acetate Infrared spectroscopic analysis 3250-2500 cm-1 y- v NH3 +
Disappearance of the CN band 1605 cm-1: v C = C (aromatic) 1 ~ ~ ~ Q ~~

Proton NMR spectroscopic analysis (300 MHz, DMSO dg, 8) 1.14 ppm (triplet, 3H): CH3 (a) Ja-b = 7.04 Hz 1.67 ppm (multiplet, 6H): CH2 (c), CH2 (2) and CH2 (3) 2.63 ppm (multiplet, 7H): CH2 (b), CH (d), CH (1) and CH2 (4) 6.81-7.11 ppm (multiplet, 3H): Aromatic H
8.00 ppm (multiplet, 3H): NH3 +
Elementary analysis Calculated: C: 70.12% H: 9.25% N: 5.83% CI: 14.79 Found: C: 70.40% H: 8.96% N: 5.83% CI: 14.69 1o PREPARATION 2: 2- (5-ETHYL-BENZO [b] THIOPHEN-3-YL) ETHYLAMINE
STAGE A: 4-ETHYL BENZENE THIOL
ab SH
Reagents 4-Ethylbenzene sulfonic acid chloride: 0.024 mole (5g) t5 Mixed aluminum and lithium hydride: 0.096 mole (3.6 g) Anhydrous tetrahydrofuran: 20 cm3 Procedure In a 100 cm3 flask, add 3.6 g of hydride with magnetic stirring mixed aluminum and lithium to 20 cm3 of anhydrous tetrahydrofuran. Cool in a bath of 2o ice then add drop by drop 5 g of 4-ethyl acid chloride benzene sulfonic.
Shake for 3 h.
Pour the reaction mixture into ice. Extract the aqueous phase by three volumes of ether. The organic phases are washed with water, dried over sulphate magnesium then evaporated to dryness.
The oil obtained is chromatographed on a column.
Characteristics 138.23 g / mole for C8H1OS
Colorless oil Rf = 0.85 in acetone-toluene-cyclohexane (2-2-1) ~~ .fi r ~ 39 Yield: 70 Infrared spectroscopic analysis 3080 cm-1: v aromatic CH
2960-2860 cm-1 ~ v CH alkyls 2560 cm-1 ~ v SH
1490 cm-1 ~ v C = Aromatic C
Proton NMR spectroscopic analysis (80 MHZ, DMSO dg, â) 1.25 ppm (triplet, 3H): CH3 (a), Ja_b = 7.80 Hz 2.65 ppm (quintuplet, 2H): CH2 (b), Jb-a = 7.80 Hz 3.40 ppm (singlet, 1: SH (attenuated in D20) H) 7.20 ppm (multiplet, 4H): Aromatic H

STAGE B: ETHYL 4-ETHYL-PHENYL-THIOACETOACETATE
abd ~ ef CH3 CH2 / O ~ ~ CHZ-CO-CH2-CH3 VS
w ~ S ~ CH2.
Reagents ~ 5 4-ethyl-benzene-thiol (Stage A): 0.025 mole (3.2 g) Ethyl 4-chloroacetoacetate: 0.026 mole (4.2 g) Pyridine: 0.1 mole (8 cm3) Anhydrous ether: 10 cm3 Procedure 2o In a 100 cm3 flask, with magnetic stirring, 3.2 g of 4-ethyl-benzene-thiol and 8 g of pyridine are dissolved in 10 cm3 of anhydrous ether. 4.2 g of 4-chloro ethyl acetoacetate are added dropwise.
The solution is stirred for 2 h at room temperature and then poured into ice.
The organic phase is extracted, washed with water, dried over sulphate magnesium then 25 evaporated to dryness.
The oil obtained is purified by column chromatography.
Characteristics 266.22 g / mole for C14H1803S
Colorless oil Rf = 0.56 in ether-hexane-petroleum ether (2-2-1) Yield: 50 Infrared spectroscopic analysis 2960-2860 cm-1 ~ v CH alkyls Disappearance of the HS band 1740 cm-1 ~ v CO ester 1710 cm-1 ~ v CO ketone 1490 cm-1 vv C = Aromatic C
Proton NMR spectroscopic analysis (80 MHz, DMSO dg, 8) l0 1.20 ppm (multiplet, CH3 (a) and CH3 (f) 6H):

2.65 ppm (quintuplet, CH2 (b), Jb_a = 7.90 Hz 2H):

3.70 ppm (singlet, CH2 (c) 2H):

3.75 ppm (singlet, CH2 (d) 2H):

4.20 ppm (quintuplet, CH2 (e), Je-f = 7.90 Hz 2H):

ts 7.20 ppm (multiplet, aromatic H
4H):

STAGE C: (5-ETHYL-BENZO [b] THIOPHEN-3-YL) ETHYL ACETATE
ab CH3 CH2 4 ~ d e ' ~ CO-CH2 (: H3 Reagents Ethyl 4-Ethyl-phenyl-thioacetoacetate (stage B): 0.012 mole (3 g) 2o Polyphosphoric acid: 30 g Toluene: 25 cm3 Phosphorus pentoxide: 0.7 g Procedure In a 250 cm3 flask containing 30 g of polyphosphoric acid, add 25 cm3 25 of toluene then 0.7 g of phosphorus pentoxide. 4-ethyl-phénylthioacétoacétate ethyl is then added all at once and the reaction mixture stirred for 5 h at a temperature of 50 ° C.
The reaction medium is poured into ice. The aqueous phase is extracted by 3 volumes of ether. The organic phases are combined, washed with 3 volumes of water, dried on 3o magnesium sulphate then evaporated to dryness.

2 ~ ~ 9 .670 The oil obtained is purified by column chromatography.
Characteristics 248.33 g / mole for C14H1602S
Colorless oil s Rf = 0.74 eluent: ether-hexane-petroleum ether (2-2-1) Yield: 55 Infrared spectroscopic analysis 2950-2860 cm-1: v CH alkyls 1730 cm-1: u CO ester 1o Disappearance of the ketone CO band 1580 cm-1: v C = C aromatic Proton NMR spectroscopic analysis (80 MHz, DMSO dg, 8) 1.20 ppm (multiplet,: CH3 (a) and 6H) CH3 (e) 2.75 ppm (quintuplet,: CH2 (b), Jb ~ = 6.95 Hz 2H) t5 3.90 ppm (singlet, 2H): CH2 (c) 4.15 ppm (quintuplet,: CH2 (d), Jd_e = 6.90 Hz 2H) 7.20 ppm (doublet doubled, = 8.35 Hz, Jmta - 1.40 1 H): Hg, Jortho Hz 7.60 ppm (multiplet,: H2 and H4 2H) 7.90 ppm (doublet, 1: H7, Jortho = 8.35 Hz H) 2o Analysis lmentaire Calculation H: 6.49% O: 12.88 : VS
: 67.70 %

Found: C: 67.64% H: 6.54% O: 12.88 STAGE D: ACID 2- (5-ETHYL-BENZO [b] THIOPHEN-3-YL) ACETIG1UE
ab CH3 CHZ j CH2 COOH
S ~ 2 _.
2s Reagents (5-Ethyl-benzo [b] thiophen-3-yl) ethyl acetate (stage C): 0.012 mole (3 g) 20% aqueous sodium hydroxide solution: 5 cm3 Methanol: 10 cm3 Procedure In a 50 cm3 flask, 3 g of 2- (5-ethyl-benzo [b] thiophene-3-yl) acetate ethyl are dissolved in 10 cm3 of methanol. Add 5 cm3 of an aqueous solution of soda to 20%. The reaction mixture is stirred at room temperature for 14 h.
Pour into 50 cm3 of water then extract with 2 volumes of ether.
The aqueous phase is acidified by addition of an acid solution concentrated hydrochloric (up to pH 3-4).
The precipitate which forms is drained and then recrystallized.
Characteristics to 220.28 g / mole for C12H1202S
White powder Melting temperature: 125-127 ° C
Rf = 0.74, eluent: ether-hexane-petroleum ether (2-2-1) Recrystallization solvent: 95 ° alcohol-water (1-7) t5 Yield: 50 Infrared spectroscopic analysis 3200-2900 cm-1: v OH acid 2960-2840 cm-1: v CH alkyls 1705 cm-1: v acidic CO
2o Disappearance of the CO ester band Proton NMR spectroscopic analysis (300 MHz, DMSO dg, b) 1.18 ppm (triplet, 3H): CH3 Ja_b - 7.58 Hz (at) 2.78 ppm (quintuplet, 2H): CH2 Jb_a _ 7.58 Hz (B) 3.89 ppm (singlet, 2H): CH2 (vs) 25 7.22 ppm (multiplet, 1: H6 H) 7.36 ppm (singlet, 1 H): H2 7.56 ppm (multiplet, 1 H): H4 7.76 ppm (multiplet, 1 H): H7 Jortho 833 Hz -

9.50-10.50 ppm (solid, 1: COOH
H) 3o Elementary analysis Calculation: C: 65.42% H: 5.49 S: 14.56 O: 14.53 %%

Found: C: 65.32% H: 5.53 S: 14.65 O: 14.50 %%

STAGE E. (5-ETHYL-BENZO [b] thiophen-3-yl) acetamide 26 21 ~ 7 ~~ 9 Reagents 2- (5-ethyl-benzo [bJthiophen-3-yl) acetic acid (Stage D): 0.006 mole (1.4 g) Thionyl chloride: 0.024 mole (2.9 g) Chloroform: 15 cm3 28% ammonia solution: 25 cm3 ab CH3 CHZ 4 CH C ~ ~

S

Procedure 1.4 g of 2- (5-ethyl benzo [b] thiophen-3-yl) acid in a 100 cm3 flask acetic 1o are dissolved with magnetic stirring in 15 cm3 of chloroform. 2.86 g chloride thionyl are added dropwise.
The solution is stirred for 3 h at room temperature and then evaporated under vacuum.
The residue is taken up in 30 cm3 of ether and then filtered on paper.
The filtrate is cooled in an ice bath.
25 cm3 of a 28% ammonia solution are then added all at once.
The precipitate is drained and then recrystallized.
Characteristics 219.29 g / mole for C12H13NOS
White powder 2o Melting temperature: 201-203 ° C
Rf = 0.35, eluent: acetone-toluene-cyclohexane (5-3-2) Recrystallization solvent: hexane Yield: 65 Infrared spectroscopic analysis 3340 and 3160 cm-1 -: v NH2 amide 2940-2840 cm-1: v CH alkyls Disappearance of the acidic CO band 1650 cm-1: v CO amide Proton NMR spectroscopic analysis (80 MHz, DMSO dg, b) 1.25 ppm (triplet, 3H): CH3 (a) Ja-b - 7.40 Hz ~ 1FI? Q39 2.75 ppm (quintuplet,: CH2 Jb-a - 7.40 2H) (b) Hz 3.60 ppm (singlet, 2H): CH2 (vs) 7.00 ppm (multiplet, 2H): NH2 7.20 ppm (doublet doubled,: Hg Jortho - 830 Hz 1 H) Jmta - 1.40 Hz 7.50 ppm (singlet, 1: H2 H) 7.65 ppm (doublet, 1 H): H4 Jmta - 1.40 Hz 7.85 ppm (doublet, 1 H): H7 Jortho - 8.30 Hz Analysis lmentaire 1o Calculation H: 5.97% N: 6.39 : VS
: 65.72 %

Found H: 6.05% N: 6.59 : VS
: 65.91 %

STAGE F. (5-ETHYL-BENZO [b] thiophen-3-YL ~ ACETONITRILE
ab CH3 CH2 d CH2 CN
6, ~ sJ 2 Reagents ~ 5 (5-Ethyl benzo [b] thiophen-3-yl) acetamide (Stage E): 0.0011 mole (0.25 g) Triethylamine: 0.0025 mole (0.25 g) Trifluoroacetic anhydride: 0.0012 mole (0.27 g) Anhydrous tetrahydrofuran: 5 cm3 2o Procedure In a 50 cm3 flask, dissolve 0.25 g of 2- (5-ethyl benzo [b] thiophen-3-yl) acetamide in 5 cm3 of anhydrous tetrahydrofuran then add 0.25 g of triethylamine.
Cool the reaction mixture in an ice-salt bath and add drop to 0.27 g drop 25 of trifluoroacetic anhydride.
Stir the solution for 1 h then evaporate in vacuo.
The residue is taken up in water and the precipitate drained and then recrystallized.
Characteristics 201.28 g / mole for C12H11NS
3o White powder Melting point: 59-60 ° C

Rf = 0.82, eluent: acetone-toluene-cyclohexane (5-3-2) Yield: 62 Recrystallization solvent: 95 ° alcohol-water (4-1) Infrared spectroscopic analysis Disappearance of NH2 bands of amide 2940-2830 cm-1: v CH alkyls 2230 cm-1: v CN
Disappearance of the amide CO band Proton NMR spectroscopic analysis (80 MHz, DMSO dg, b) 1.25 ppm (triplet, 3H): CH3 (a) Ja-b _ 7.50 Hz 2.80 ppm (quintuplet, 2H): CH2 (b) Jb-a _ 7.50 Hz 4.25 ppm (singlet, 2H): CH2 (c) 7.30 ppm (doublet doubled,: H6 Jortho - 8.30 Hz 1 H) Jmta - 1.30 Hz 7.70 ppm (multiplet, 2H): H2 and 7.95 ppm (doublet, 1 H): H7 Jortho - 8.30 Hz Elemental analysis Calculation: C: 71.60% H: 5.51% N: 6.96 Found: C: 71.78% H: 5.68% N: 6.99 2o STAGE G. 2- (5-ETHYL-BENZO [b] thiophen-3-yl) ETHYLAMINE

ab CH3 CHz 4 ~ NH
~ z d Reagents (5-Ethyl-benzo [b] thiophen-3-yl) acetonitrile (stage F): 0.004 mole (0.7 g) Lithium aluminum hydride: 0.01 mole (0.4 g) Aluminum chloride: 0.01 mole (1.4 g) Anhydrous ether: 25 cm3 Procedure In a 100 cm3 flask containing 25 cm3 of anhydrous ether, add under agitation magnetic 0.4 g lithium aluminum hydride, 1.4 g chloride aluminum then 0.7 g of (5-ethyl-benzo [b] thiophen-3-yl) acetonitrile.
After 30 min, hydrolyze the reaction mixture on ice and add 20 cm3 20% aqueous sodium hydroxide solution.
The ethereal phase is extracted, washed with 2 volumes of water, dried over sulphate magnesium then filtered on paper.
Bubble a stream of gaseous hydrochloric acid into the solution and wring it out 1o precipitate formed The hydrochloride is purified by trituration in cyclohexane.
Characteristics (hydrochloride) 241.77 g / mole for C12H16CINS
White powder Melting temperature: 159-161 ° C
Rf = 0.15, eluent: acetone-toluene-cyclohexane-triethylamine (5-3-2-1) Yield: 50 Infrared spectroscopic analysis 3240-2600 cm-1: v NH3 +
2o Disappearance of the CN band Proton NMR spectroscopic analysis (80 MHz, CDCI3, 8) 1.30 ppm (triplet, CH3 (a) Ja_b = 7.50 Hz 3H):

2.75 ppm (quintuplet, CH2 (b) Jb_a = 7.50 Hz 2H):

3.15 ppm (multiplet, CH2 (c) and CH2 (d) 4H):

7.20 ppm (multiplet, H6 Jonho = 8.35 Hz 1 H):

7.50 ppm (multiplet, H2 1 H):

7.70 ppm (multiplet, H4 1 H):

7.95 ppm (doublet, H7 Jortho = 8.35 Hz 1 H):

8.20 ppm (multiplet, NH3 +
3H):

3o Analysis lmentaire Calculation H: 6.67% N: 5.79% CI: 14.66 : VS :
59.61 %

Found: C: 59.78 H: 6.78% N: 5.47% CI: 14.28 %

PREPARATION 3. (R, S) 2- (7-METHYL-1,2,3,4-TETRAHYDRO-NAPHT-1-YL) ETHYLAMINE
Proceeding as in preparation 1 but starting with toluene instead of ethylbenzene, the title compound is obtained.
PREPARATION 4. (R, S) 2- (7-PROPYL-1,2,3,4-TETRAHYDRO-NAPHT-1-YL) ETHYLAMINE
By proceeding as in preparation 1, but replacing ethylbenzene through propylbenzene, the title compound is obtained.
PREPARATION 5. (R, S) 2- (7-BUTYL-1,2,3,4-TETRAHYDRO-NAPHT-1-YL) 1 o ETHYLAMINE
By proceeding as in preparation 1, but replacing ethylbenzene speak butylbenzene, the title compound is obtained. __ PREPARATION 6. (R, S) 2- (5-METHYL-INDOL-3-YL) ETHYLAMINE
(from Biosci., Biotechnol., Biochem. 1993, 57 (7), pp 1210-11) t 5 PREPARATIONS 7 TO 12 By proceeding as in preparation 2 but using the reagents appropriate, the following preparations are obtained PREPARATION 7. 2- (5-PROPYL-BENZO [b] thiophen-3-YL) ETHYLAMINE
PREPARATION 8. 2- (5-BUTYL-BENZO [b] thiophen-3-YL) ETHYLAMINE
2o PREPARATION 9. 2- (5-hexyl-BENZO [b] thiophen-3-YL) ETHYLAMINE
PREPARATION 10. 2- (5-cyclopropyl-BENZO [b] thiophen-3-YL) ETHYLAMINE
PREPARATION 11. 2- (5-cyclobutyl-BENZO [b] thiophen-3-YL) ETHYLAMINE
PREPARATION 12. 2- (5-cyclopropylmethyl-BENZO [b] thiophen-3-yl) ETHYLAMINE

3, ~~ 67a ~ a EXAMPLE 1: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
ACETAMIDE
d e ab ~ ~ NH-CO-CH3, 6 ~ 3 s Reagents (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) hydrochloride ethylamine: 0.008 mole (2 g) Acetyl chloride: 0.009 mole (0.7 g) Potassium carbonate: 0.024 mole (3.3 g) 1o Chloroform: 20 cm3 Water: 10 cm3 Dissolve (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-) hydrochloride yl) ethylamine of preparation 1 in a water-chloroform mixture (10 - 20) then add 3 potassium carbonate equivalents. Cool in an ice-salt bath.
Under strong t5 magnetic stirring, add 1.2 equivalents of chloride dropwise acetyl.
Stirring is continued for 45 min.
The chloroform phase is extracted, washed with an acid solution hydrochloric 1 N then to water, dried over magnesium sulfate and evaporated to dryness.
The residue obtained is purified by chromatography.
2o Characteristics 245.35 g / mole for C16H23N0 Colorless oil Rf = 0.43, eluent: acetone-toluene-cyclohexane (5-3-2) Yield: 62 2s Infrared spectroscopic analysis 3260 cm-1 v NH amide :

3060 cm-1 v aromatic CH
:

2980-2840 cm-1 v CH alkyls :

1630 cm-1 v CO amide :

30 1540 cm-1 v C = C aromatic :

Proton NMR spectroscopic analysis (300 MHz, DMSO dg, â) 1.21 ppm (triplet, 3H) CH3 (a), Ja_b = 7.60 Hz :

1.80 ppm (multiplet, CH2 (2), CH2 (3) and CH2 (c) 6H):

1.96 ppm (singlet, 3H) CH3 (e) :

2.58 ppm (quintuplet, CH2 (b), Jb_a = 7.60 Hz 2H):

2.72 ppm (multiplet, CH2 (4) 2H):

2.81 ppm (multiplet, CH (1) 1 H):

3.37 ppm (multiplet, CH2 (d) 2H);

5.63 ppm (multiplet, NH amide 1 H):

6.96 ppm (multiplet, aromatic H
3H):

Analysis lmentaire Calculation H: 9.45% N: 5.71 : VS :
78.32 %

Found: C: 77.97% H: 9.43% N: 5.59 EXAMPLE 2: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
t5 BUTYRAMID
By proceeding in the same way as in Example 1, but by replacing the acetyl chloride with butyryl chloride, the compound of title.
~ NH-CO-CH2 CH2-CH3 Reagents 2o (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) hydrochloride ethylamine: 0.008 mole (2 g) Butyryl chloride: 0.009 mole (1 g) Potassium carbonate: 0.024 mole (3.3 g) Chloroform: 20 cm3 25 Water -: 10 cm3 Characteristics 273.40 g / mole for C18H27N0 White powder Fusiorry temperature-54-56 ° C
3o Yield: 75 purified by column chromatography in ethyl acetate EXAMPLE 3: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL] CYCLO-PROPANECARBOXAMIDE
d ab ~ ~ NH-CO--CH3 CHZ e, z 6 \ 3 5 By proceeding in the same way as in Example 1, but by replacing the acetyl chloride with cyclopropane carboxylic acid chloride, get the composed of the title.
Reagents (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronaphthalene) hydrochloride 1o ethylamine: 0.008 mole (2 g) Cyclopropane carboxylic acid chloride: 0.009 mole (1 g) Potassium carbonate: 0.024 mole (3.3 g) Chloroform: 20 cm3 Water: 10 cm3 ~ s Features 271.39 g / mole for C18H25N0 White powder Melting temperature: 95-97 ° C
Efficiency: 80%
2o Recrystallization solvent: hexane EXAMPLE 4: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
trifluoroacetamide d ab ~ -NH-CO-CF3 CH3 CH2 g ' / z 6 \ 3 Reagents 25 (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) hydrochloride ethylamine: 0.008 mole (2 g) ~~~ s ~ o ~ 9 Trifluoroacetic anhydride: 0.009 mole (2 g) Pyridine: 10 cm3 In a 50 cm3 flask, dissolve under magnetic stirring 2 g of the hydrochloride (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine in 10 cm3 of pyridine.
Cool the reaction mixture in ice.
Add 2 g of trifluoroacetic anhydride drop by drop. Continue restlessness for 30 min. Pour into ice. The aqueous phase is extracted by 3 volumes of ether. The organic phases are combined, washed with 3 volumes of water, dried over sulfate magnesium then evaporated under vacuum.
1o The residue obtained is purified by column chromatography then recrystallized Characteristics 299.33 g / mole for C16H2pF3N0 White powder Melting temperature: 66-69 ° C
Yield: 60 purified by column chromatography (eluent-ethyl acetate) Recrystallization solvent: hexane Analysis spectroscopic in infrared 3280 cm-1: v NH amide 3070 cm-1: v aromatic CH

2960-2840 cm-1: v CH alkyls 1630 cm-1: v CO amide 1550 cm-1: v aromatic CC

Analysis (300 MHz, CDCI3, 8) spectroscopic of NMR

1.21 ppm (triplet, 3H): CH3 (a) Ja_b = 7.59 Hz 1.85 ppm (multiplet, 6H): CH2 (c), CH2 (2) and CH2 (3) 2.58 ppm (quintuplet,: CH2 (b) Jb_a = 7.59 Hz 2H) 2.73 ppm (multiplet, 2H): CH2 (4) 2.84 ppm (multiplet, 1: CH (1) H) 3.74 ppm (multiplet, 2H): CH2 (d) 6.52 ppm (multiplet, 1: NH
H) 6.97 ppm (multiplet, 3H): Aromatic H

Elementary analysis Calculated: C: 64.20% H: 6.74% N: 4.68% F ~: 19.04 Found: C: 64.13% H: 6.70% N: 4.62% F ~: 18.78 EXAMPLE 5: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
valeramide at 9 a.m.
ab ~ -NH-CO-CH2 CH2 CH2 CH3 6 ~ 3 By proceeding in the same way as in example 1, but by replacing the acetyl chloride with valeryl chloride, the compound of title.
Reagents 1o (R, S) 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) hydrochloride ethylamine: 0.008 mole (2 g) Valeryl chloride: 0.009 mole (1.1 g) Potassium carbonate: 0.024 mole (3.3 g) Chloroform: 20 cm3 t 5 Water: 10 cm3 Characteristics 287.43 g / mole for C18H2gN0 Colorless oil Yield: 65 2o purified by column chromatography in ethyl acetate Infrared spectroscopic analysis 3290 cm-1: v NH amide 2990-2820 cm-1: v CH alkyls 1630 cm-1: v C = O amide 25 1530 cm-1: v C = C aromatic NMR spectroscopic analysis (300 MHz, CDCI3, 8) 0.91 ppm (triplet, 3H): CH3 (h), Jh_g = 7.29 Hz 1.21 ppm (triplet, 3H): CH3 (a), Ja_b = 7.59 Hz ~~ ~~ s7o 1.33 ppm (multiplet, CH2 (g) 2H):

1.75 ppm (multiplet, CH2 (2), CH2 (3), CH2 (c), 8H): CH2 (f) 2.15 ppm (triplet, 2H) CH2 (e), JQ_f = 7.57 Hz :

2.58 ppm (quintuplet, CH2 (b), Jb_a = 7.59 Hz 2H):

2.71 ppm (multiplet, CH2 (4) 2H):

2.80 ppm (multiplet, CH (1 1 H):

3.37 ppm (multiplet, CH2 (d) 2H):

5.71 ppm (multiplet, NH
1 H):

6.97 ppm (multiplet, aromatic H
3H):

1o EXAMPLES 6 TO 12 By proceeding in the same way as in Example 1, but using the chloride acyl or appropriate iso (thio) cyanate, the following examples are obtained EXAMPLE 6: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL] CYCLO-butylcarboxamide EXAMPLE 7: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
PROPIONAMIDE
EXAMPLE 8: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
isobutyramide EXAMPLE 9: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
2o N'-METHYLUREE
EXAMPLE 10: (R, S) N- [2- (7-ETMYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
N'-propylurea EXAMPLE 11: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
N'-cyclopropylurea EXAMPLE 12: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1YL) ETHYL]
N'-CYCLOBUTYLUREE
EXAMPLE 13: (R, S) N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOBUTANE-CARBOXAMIDE

~ 1676 ~ 9 By proceeding in the same way as for the amidation reaction of example 1, but replacing 2- (7-ethyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine with 2- (5-ethyl benzo [b] thiophen-3-yl) ethylamine (preparation 2) and acetyl chloride by chloride cyclobutane carboxylic acid, the title compound is obtained.
abf CH3 CH2% ~ NH-CO E (\, g J 2 d f.
Reagents 2- (5-ethyl benzo [b] thiophen-3-yl) hydrochloride ethylamine: 0.001 mole (0.25 g) Potassium carbonate: 0.003 mole (0.4 g) Cyclobutane carboxylic acid chloride: 0.0013 mole (0.16 g) chloroform: 16 cm3 Water: 8 cm3 Characteristics 286.40 g / mole for C17H2pNOS
White powder Melting temperature: 105-107 ° C
Rf = 0.70, eluent: acetone-toluene-cyclohexane (5-3-2) Recrystallization solvent: hexane 2o Yield: 70 Analysis spectroscopic in infrared 3275 cm-1: v NH amide 3070 cm-1: u aromatic CH

2980-2840 v CH alkyls cm-1 :

1630 cm-1: u CO amide 1550 cm-1: v C = Aromatic C

Analysis spectroscopic of NMR
proton (300 MHz, DMSO
dg, 8) 1.25 ppm (triplet,: CH3 (a) Ja_b = 7.53 Hz 3H) 1.97 ppm (multiplet ,: CH2 (f), CH2 (f ') and CH2 (g) 6H) 2.57 ppm (quintuplet ,: CH2 (b) Jb_a = 7.53 Hz 2H) 2.95 ppm (multiplet ,: CH2 (c) 3H) 167Q ~ 9 ~

3.36 ppm (multiplet ,: CH2 (d) 2H) 7.25 ppm (multiplet ,: H6 ~ ortho = 8.27Hz 1 H) 7.40 ppm (singlet,: H2 1 H) 7.68 ppm (multiplet ,: H4 1 H) 7.85 ppm (multiplet,: H7 and NH
2H) Analysis lmentaire Calculation H: 7.04% N: 4.89% CI: 11.20 : VS
: 71.29 %

Found: C: 70.88 H: 7.32% N: 4.90% CI: 11.02 %

EXAMPLE 14: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
1o By proceeding in the same way as for the synthesis of the compound of the example but replacing the chloride of cyclobutane carboxylic acid with the acetyl chloride, the title compound is obtained.
Characteristics 247.36 g / mole for C14H17NOS
~ 5 melting temperature: 87-88 ° C

Starting from N- [2- (5-ethyl-benzothiophen-3-yl)] ethylamine, but in employing the acid chloride or the appropriate isocyanate, the following examples are obtained EXAMPLE 15 N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
2o Melting temperature: 62-64 ° C
EXAMPLE 16: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIONAMIDE
Melting temperature: 92-93 ° C
EXAMPLE 17: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
Melting temperature: 61-63 ° C
EXAMPLE 18: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOPROPANE-CARBOXAMIDE
Melting temperature ~ 9? -94 ° C

21. ~~ ~ 7 9 EXAMPLE 19: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOHEXANE-CARBOXAMIDE
EXAMPLE 20 N-[2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYLUREE
Melting temperature: 137-139 ° C
EXAMPLE 21: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYLUREE
Melting temperature: 133-135 ° C
EXAMPLE 22 N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-ETHYLUREE
EXAMPLE 23: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-CYCLOPROPYL-to UREE
EXAMPLE 24: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-CYCLOHEXYLUREE
EXAMPLE 25: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] TRIFLUORO
ACETAMIDE
EXAMPLE 26 N- [2- (5-METHYL-INDOL-3-YL) ETHYL] ACETAMIDE
By proceeding in the same way as for the amidation reaction of example 1, using as reagents 5-methyl tryptamine (preparation 5) and acetyl chloride, the title compound is obtained.

Starting from 5-methyl-tryptamine but using acyl chloride or the appropriate isocyanate, the following examples are obtained EXAMPLE 27 N- [2- (5-METHYL-INDOL-3-YL) ETHYL) CYCLOPROPANECARBOXAMIDE
EXAMPLE 28 N- [2- (5-METHYL-INDOL-3-YL) ETHYL] BUTYRAMIDE
EXAMPLE 29: N- [2- (5-METHYL-INDOL-3-YL) ETHYL] TRIFLUOROACETAM ~ DE
EXAMPLE 30: N- [2- (5-METHYL-INDOL-3-YL) ETHYL] N'-METHYLUREE

EXAMPLE 31: N- [2- (5-METHYL-INDOL-3-YL) ETHYL] N'-PROPYLUREE
EXAMPLE 32: (R, S) N- [2- (7-METHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
ACETAMIDE
By proceeding in the same way as for the amidation reaction of the compound of Example 1, but using as reagents (R, S) 2- (7-methyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine (preparation 3) and acetyl chloride, get the composed of the title.

Starting from 2- (7-methyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine, but in 1o using the appropriate acyl chloride or isocyanate, the following examples EXAMPLE 33: (R, S) N- [2- (7-METHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]

EXAMPLE 34: (R, S) N- [2- (7-METHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-methylurea ~ 5 EXAMPLE 35: (R, S) N- [2- (7-METHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-propylurea EXAMPLE 36: (R, S) N- [2- (7-METHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
butyramide EXAMPLE 3? : (R, S) N- [2- (7-PROPYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
2o ACETAMIDE
By proceeding in the same way as during the amidation reaction of the compound of Example 1, but using as reagent (R, S) 2- (7-propyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine (preparation 4), the compound of title.

2s Starting from (R, S) 2- (7-propyl-1,2,3,4-tetrahydronapht-1-yl) ethylamine, but in using the appropriate acid chloride or isocyanate, the following examples 216? Q39 EXAMPLE 38: (R, S) N- [2- (7-PROPYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
cyclopropanecarboxamide EXAMPLE 39: (R, S) N- [2- (7-PROPYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-methylurea EXAMPLE 40: (R, S) N- [2- (7-PROPYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-propylurea EXAMPLE 41: (R, S) N- [2- (7-PROPYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
trifluoroacetamide 1o EXAMPLE 42: (R, S) N- [2- (7-BUTYL-1,2,3,4-TETRAHYDRO-NAPHT-1-YL) ETHYL]
ACETAMIDE
By proceeding in the same way as for the amidation reaction of the compound of Example 1, but using as reagent 2- (7-butyl-naphth-1-yl) ethylamine (preparation 5), the title compound is obtained.

Starting from 2- (7-butyl-1,2,3,4-tetrahydronapht-1- ~ yl) ethylamine, but in using the appropriate acid chloride or isocyanate, the following examples EXAMPLE 43: (R, S) N- [2- (7-BUTYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-methylurea 2o EXAMPLE 44: (R, S) N- [2- (7-BUTYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-propylurea EXAMPLE 45: (R, S) N- [2- (7-BUTYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
cyclopropanecarboxamide EXAMPLE 46: (R, S) N- [2- (7-BUTYL-1,2,3,4-TETRAHYDRONAPHT 1YL) ETHYL]
trifluoroacetamide Using preparations 1 and 2 but using isothiocyanates appropriate, the compounds of the following examples are obtained EXAMPLE 47: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL]
N'-methylthiourea EXAMPLE 48: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL] N'-Ethyl-THIOUREA
EXAMPLE 49: (R, S) N- [2- (7-ETHYL-1,2,3,4-TETRAHYDRONAPHT-1-YL) ETHYL] N'-PROPYL-THIOUREA
EXAMPLE 50: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYLTHIOUREE
1o EXAMPLE 51: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-ETHYLTHIOUREE
EXAMPLE 52: N- [2- (5-ETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYLTHIOUREE

By proceeding as described above but starting from preparations 7 to the compounds of the following examples are obtained EXAMPLE 53: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
EXAMPLE 54: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIONAMIDE
EXAMPLE 55: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
EXAMPLE 56: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
EXAMPLE 57: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOPROPANE-CARBOXAMIDE -EXAMPLE 58: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOBUTANE-CARBOXAMIDE
EXAMPLE 59: N- [2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYLUREE

~ 1 ~ '~~ 39 , .. 43 EXAMPLE 60 N-[2- (5-PROPYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYLUREE
EXAMPLE 61: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
EXAMPLE 62: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIONAMIDE
EXAMPLE 63: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
EXAMPLE 64: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
EXAMPLE 65 N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOPROPANE-CARBOXAMIDE
EXAMPLE 66: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOBUTANE-CARBOXAMIDE
to EXAMPLE 67: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYLUREE
EXAMPLE 68: N- [2- (5-BUTYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYLUREE
EXAMPLE 69: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
EXAMPLE 70: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIONAMIDE
EXAMPLE 71: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
~ 5 EXAMPLE 72: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
EXAMPLE 73: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOPROPANE-CARBOXAMIDE
EXAMPLE 74: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOBUTANE-CARBOXAMIDE
2o EXAMPLE 75: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYLUREE
EXAMPLE 76: N- [2- (5-HEXYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYLUREE

EXAMPLE 77: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
EXAMPLE 78: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIO-NAMIDE
EXAMPLE 79 ': N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
EXAMPLE 80: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
EXAMPLE 81: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLOPRO-PANECARBOXAMIDE
EXAMPLE 82: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLO-BUTANECARBOXAMIDE
to EXAMPLE 83: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYL-UREA
EXAMPLE 84: N- [2- (5-CYCLOPROPYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYL-UREA
t5 EXAMPLE 85: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] ACETAMIDE
EXAMPLE 86: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] PROPIO-NAMIDE
EXAMPLE 87: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] BUTYRAMIDE
EXAMPLE 88: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] VALERAMIDE
2o EXAMPLE 89: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLO-PROPANECARBOXAMIDE
EXAMPLE 90: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] CYCLO-BUTANECARBOXAMIDE

~ 1 ~ '~~~ 9 EXAMPLE 91: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-METHYL-UREA
EXAMPLE 92: N- [2- (5-CYCLOBUTYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-PROPYL-UREA
EXAMPLE 93: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
ACETAMIDE
EXAMPLE 94: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
PROPIONAMIDE
EXAMPLE 95: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
to BUTYRAMIDE
EXAMPLE 96: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
valeramide EXAMPLE 97: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
cyclopropanecarboxamide EXAMPLE 98: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL]
cyclobutanecarboxamide EXAMPLE 99: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-methylurea EXAMPLE 100: N- [2- (5-CYCLOPROPYLMETHYL-BENZOTHIOPHEN-3-YL) ETHYL] N'-2o PROPYLUREE
EXAMPLE 101: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] ACETAMIDE
EXAMPLE 102: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] CYCLOPROPANECARBOXAMIDE
EXAMPLE 103: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] CYCLOBUTANE CARBOXAMIDE
EXAMPLE 104: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] TRIFLUOROACETAMIDE

~? û '~~ 39 EXAMPLE 105: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] N'-METHYLUREE
EXAMPLE 106: N- [2- (7-ETHYL-NAPHT-1-YL) ETHYL] N'-PROPYLUREE
EXAMPLE 107: N- [2- (7-METHYL-NAPHT-1-YL) ETHYL] ACETAMIDE
EXAMPLE 108: N- [2- (7-PROPYL-NAPHT-1-YL) ETHYL] ACETAMIDE
EXAMPLE 109: N- [2- (7-BUTYL-NAPHT-1-YL) ETHYL] ACETAMIDE
EXAMPLE 110: N- [2- (7-HEXYL-NAPHT-1-YL) ETHYL] ACETAMIDE
PHARMACOLOGICAL STUDY
1o EXAMPLE A: STUDY OF ACUTE TOXICITY
Acute toxicity was assessed after oral administration in batches of 8 mouse (26 ~ 2 grams). The animals were observed at regular intervals during the first one daily and daily for two weeks after treatment. The DL 50, resulting in the death of 50% of the animals, was evaluated. ' The LD 50 of the products tested is greater than 1000 mg.kg-1 for the compounds studied which indicates the low toxicity of the compounds of the invention.
EXAMPLE B: STUDY OF BINDING TO MELATONIN RECEPTORS
B1) STUDY ON CELLS OF THE TUBERALIS PARS OF SHEEP
Melatonin receptor binding studies the invention have 2o were carried out according to conventional techniques on the cells of the pars mutton tuberalis.
The pars tuberalis of the adenohypophysis is indeed characterized, in mammals by a high density of melatonin receptors (Journal of Neuroendocrinology vol. (1), pp 1-4 (1989)).
PROTOCOL
1) Tuberalis pars membranes from sheep are prepared and used as fabric target in saturation experiments to determine the capabilities and binding affinities for 2- [1251] - iodomelatonin.

47 ~ 1 ~~~~~
2) Sheep's Pars tuberalis membranes are used as target tissue, with the different compounds to be tested, in competitive binding experiments by compared to the 2- [1251) - melatonin.
Each experiment is carried out in triplicate and a range of concentrations different is tested for each compound.
The results make it possible to determine, after statistical processing, the affinities of binding of the test compound.
RESULTS
It appears that the compounds of the invention have a powerful affinity for the io melatonin receptors superior to melatonin itself.
B2) STUDY ON MEMBRANES OF CHICKEN BRAIN CELLS
(GALLUS DOMESTICUS) The animals used are chickens (Gallus domesticus) aged 12 days.
They are sacrificed between 1 and 5 p.m. on the day of their arrival. Brains are quickly sampled and frozen at - 200 ° C then stored at - 80 ° C. The membranes are prepared according to the method described by Yuan and Pang (Journal of Endocrinology ~, pages 475-482, 1991). 2- [1251) melatonin is incubated in the presence of membranes in a solution buffered at pH 7.4 for 60 min at 25 ° C. At the end of this period, suspension membrane is filtered (Whatman GF / C). Radioactivity retained on the filter is determined 2o using a Beckman ~ LS 6000 liquid scintillation counter.
The products used are _ 2_ [1251) melatonin - melatonin current products - original molecules In primary screening, the molecules are tested at 2 concentrations (10-7 and

10-5 M). Each result is the average of n = 3 independent measurements. The molecules active ingredients selected based on the results of the primary screening a ~~ s ~ a ~~

quantitative determination of their effectiveness (1C50). They are used to 10 concentrations different.
Thus the IC50 values found for the preferred compounds of the invention, who correspond to the affinity values show that the binding of the compounds of the invention tested is very powerful.
EXAMPLE C: TEST OF THE PLATES
The products of the invention are administered by the esophageal route to batches ten io mouse. One batch receives gum syrup. 30 minutes after administration products to study, the animals are placed in cockpits whose floor includes four metal plates. Whenever the animal moves from one plate to another, it receives a slight electrical discharge (0.35 mA). The number of passages is recorded during a minute. After administration, the compounds of the invention increase significantly significant t5 the number of passages which shows the anxiolytic activity of the compounds of the invention.
EXAMPLE D: COMPOUNDS OF THE INVENTION ON CIRCADIAN RHYTHMS
RAT LOCOMOTOR ACTIVITY
The involvement of melatonin in training, by alternation day / night, from most physiological, biochemical and behavioral circadian rhythms allowed 2o to establish a pharmacological model for the search for ligands melatoninergic.
The effects of molecules are tested on many parameters and in particular on circadian rhythms of locomotor activity which represent a marker reliable of endogenous circadian clock activity.
In this study, we evaluate the effects of such molecules on a model 25 particular experimental, namely the rat placed in temporal isolation (permanent darkness).
EXPERIMENTAL PROTOCOL
One month old Long Evans male rats are subjected as soon as they arrive laboratory with a light cycle of 12 hours of light per 24 hours (LD 12:12). w After 2 to 3 weeks of adaptation, they are placed in fitted cages a 3o wheel connected to a recording system to detect phases locomotor activity and thus follow the nycthemeral (LD) or circadian (DG) rhythms.
As soon as the recorded rhythms show a stable training by the cycle bright LD 12: 12, the rats are put in permanent darkness (DD).

Two to three weeks later, when free rein (rhythm reflecting that of endogenous clock) is clearly established, rats are given a daily administration of the molecule to be tested.
The observations are made thanks to the visualization of the rhythms business s - training of activity rhythms by the luminous rhythm, - disappearance of the training of rhythms in permanent darkness, - training through daily administration of the molecule; effect transient or sustainable.
Software allows - measure the duration and intensity of the activity, the period of the rhythm in animals in free course and during treatment, - possibly highlight by spectral analysis the existence of circadian and non-circadian components (ultradian for example).
RESULTS
ts It appears clearly that the compounds of the invention make it possible to act on way powerful on the circadian rhythm via the melatoninergic system.
EXAMPLE E: ANTIARYTHMIG1UE ACTIVITY
PROTOCOL
(Ref: LAWSON JW et al. J. Pharmacol. Expert. Therap. 160: 22-31, 1968) 2o The test substance is administered intraperitoneally to a group of 3 mouse 30 min before exposure to chloroform anesthesia. The animals are then observed for 15 min. The lack of recording of arrhythmias and frequency heart rates greater than 200 beats / min (control: 400-480 beats /
min) at at least two animals indicate significant protection.
25 EXAMPLE F: ANTI-AGGREGATE PLATELET ACTIVITY
PROTOCOL
(Ref.: Bertele V. et al. Science. ~ Q: 517-519, 1983 Ibid, Eur. J. Pharmacol. $ ~: 331-333, 1982) The inventive compounds (100 ~ .g / ml) are tested for their capacity inhibit irreversible platelet aggregation induced by sodium arachidonate (50 ~ g / ml) in rabbit plasma enriched in platelets.
An inhibition of more than 50% of the maximum aggregation indicates an activity significant for the compounds of the invention.
This in vitro test shows that the compounds of the invention are good candidates for the treatment of cardiovascular diseases, in particular thromboses EXAMPLE G: EXTENSION OF BLEEDING TIME
1o PROTOCOL
(Ref.: Djana E. et al. Thrombosis Research. ~: 191-197, 1979) Butler KD et al. Thromb. Haemostasis. 47: 46-49, 1982) The test compounds are administered orally (100 mg / kg) to a group of 5 mouse 1 h before standardized sectioning of the end of each tail (0.5 mm).
t5 The mice are immediately suspended vertically, the tails being 2 cm immersed in a test tube containing saline isotonic at 37 ° C.
The time required for the bleeding to stop for a period of 15 seconds is then determined.
An extension of more than 50% of the bleeding time relative to a group 2o of control animals is considered significant for the compounds of the invention.
This in vivo test confirms the advantage of the compounds of the invention for the processing cardiovascular pathologies since the compounds of the invention prolong time to bleeding.
EXAMPLE H: HYPOBARIC HYPOXIA TEST

(Ref.: Gotti B., and Depoortere H., Circ. Cerebrale, Congrès de Circulation brain, Toulouse, 105-107, 1979) The test compounds are administered intraperitoneally (100 mg / kg) to a group of 3 mice 30 minutes before being placed in a room at the hypobaric pressure of 20 cm Hg.
Extension of survival time compared to a group of treated animals with the vehicle of more than 100% in the absence of a depressant effect on the nervous system central indicates cerebroprotective activity of the compounds of the invention.
EXAMPLE 1. PHARMACEUTICAL COMPOSITION: TABLETS
1000 tablets containing 5 mg of N- [2- (5-ethyl-benzothiophen-3-yl) ethyl] acetamide N- [2- (5-ethyl-benzothiophen-3-yl) ethyl] acetamide .................................... 5 g to Starch from corn................................................. ...........................
............. 20 g Starch But................................................. ..........................
........... 20 g Lactose .................................................. .............................
.................... 30 g Stearate magnesium................................................. .....................
...... 2 g Silica................................................. ........................
................................ 1 g hydroxypropyl .................................................. ...........................
2 g

Claims (9)

1) Compounds of formula (I):

in which:
- R1 represents a radical chosen from alkyl, substituted alkyl, cycloalkyl, cycloalkyl-substituted, cycloalkylalkyle, and cycloalkylalkyle substituted - Has a group with the benzene ring to which it is linked cyclic chosen from naphthalene, benzothiophene, 2,3-dihydrobenzothiophene, indoline, substituted indoline, indole and indole substituted - R2 represents a hydrogen or an alkyl, - R3 represents:
. an R31 group:

with X representing a sulfur or an oxygen and R4 representing a hydrogen or an R41 radical chosen from alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyle and cycloalkylalkyl substituted . or a group of formula (R32):

with X 'representing a sulfur or an oxygen and R5 representing a hydrogen or a radical chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl and substituted cycloalkylalkyl, it being understood that during the description of the formula (I), and unless otherwise mentioned opposite:
- the terms "alkyl" and "alkoxy" denote linear groups or branched containing from 1 to 6 carbon atoms, - the terms "alkenyl" and "alkynyl" denote linear groups or branched containing from 2 to 6 atoms, the term "cycloalkyl" denotes a group of 3 to 8 atoms of carbon, - the term "substituted" associated with the alkyl radical signifies that this radical is substituted by one or more substituents chosen from halogen, alkyl, hydroxy and alkoxy, the term "substituted" associated with the radical "cycloalkyl" and "cycloalkylalkyle" means that this radical is substituted by one or several radicals or groups chosen from halogen, alkyl and oxo, - the term "substituted" associated with the terms "indole" and "indoline" means that these groups are substituted on the nitrogen in position 1 by a radical chosen from -Ra, -CO-Ra and -CO-O-Ra in which Ra represents an alkyl, phenyl or phenylalkyl radical, and their enantiomers and diastereoisomers. 2) Compounds of formula (I) according to claim 1 in which, taken separately or together, - R1 represents an alkyl, - R1 represents a (C2-C6) alkyl, - R1 represents an ethyl, - R1 represents a propyl, - R1 represents a butyl, - Forms with the benzene nucleus to which it is linked a naphthalene, - Forms with the benzene nucleus to which it is linked a benzothiophene, - Has an indole with the benzene nucleus to which it is linked, - Has an indole with the benzene nucleus to which it is linked substituted - R2 represents hydrogen, - R2 represents an alkyl, - R3 represents a group R3, as defined in formula (I), - R3 represents an R32 group as defined in formula (I), - R4 represents a hydrogen atom, - R4 represents an alkyl, - R4 represents a cycloalkyl, - R4 represents an alkenyl, - R5 represents a hydrogen, - R5 represents an alkyl, - R5 represents a cycloalkyl, - X represents oxygen, - X represents a sulfur, - X 'represents an oxygen, - or X 'represents a sulfur. 3) Compounds of formula (I) according to claim 1 corresponding to Respective formulas (1) to (3):

wherein R1, R2 and R3 are as defined in claim 1. 4) Compounds according to claim 1 which are:
- N- [2- (5-ethyl benzothiophen-3-yl) ethyl] acetamide, and the - N- [2- (5-ethyl benzothiophen-3-yl) ethyl] cyclobutanecarboxamide, 5) Process for the preparation of the compounds of formula (I) characterized in that than :
reacting a compound of formula (II):

in which R1 and A are as defined in claim 1, - either with formic acid or with a compound of formula (IIIa) or (IIIb):

wherein R41 is as defined in claim 1 and Hal represents a halogen, in order to obtain the compounds of formula (I / a):

in which R1, R2, R4 and A are as defined in claim 1, compounds of formula (I / a) subjected to the Lawesson reagent to obtain the compounds of formula (I / a '):

in which R1, R2, R4 and A are as defined in claim 1, either with a compound of formula (IV):

X = C = N-R5 (IV) wherein X 'and R5 are as defined in claim 1 so to obtain the compounds of formula (1 / b):

wherein R1, R2, R5, A and X 'are as defined in claim the compounds of formula (1 / a), (1 / a ') and (1 / b) forming all of the compounds of formula (I) according to claim 1, compounds of formula (I) which are, where appropriate, separated into their different enantiomers or diastereoisomers. 6) Process for the preparation of the compounds of formula (1 / f):

in which R1, R2 and R3 are as defined in claim 1, characterized in that:

reacting a compound of formula (II / b) (11 / b) in which R1 and R2 are as defined in claim 1, - either with a compound of formula (IIIa) or (IIIb) as defined in claim 5, in order to obtain the compounds of formula (I / g):

(I / 9) wherein R1, R2 and R4 are as defined in claim 1, which are then subjected to the Lawesson reagent to obtain the compounds of formula (I / g '):

(I / 9) in which R1, R2 and R4 are as defined in claim 1, - either with a compound of formula (IV) as defined in claim 5, in order to obtain the compounds of formula (I / h):

(I / h) in which R1, R2, R5 and X 'are as defined in claim 1, the compounds of formula (I / g), (I / g ') and (I / h) forming all of the compounds of formula (I / f), the compounds of formula (I / f) which can be separated into their different enantiomers or diastereoisomers. 7) Pharmaceutical compositions containing the products of formula (I) according to one of claims 1 to 4 in combination with one or more pharmaceutically acceptable excipients. 8) Pharmaceutical compositions according to claim 7 useful for the treatment of melatoninergic disorders. 9) Pharmaceutical compositions according to claim 7 useful in treatments for seasonal depression, sleep disturbances, cardiovascular pathologies, insomnia and fatigue due to lags schedules, appetite disorders and obesity.